Glycolysis the anaerobic metabolism of glucose

Overall, the pathway of glycolysis is cleavage of the six-carbon glucose molecule into two three-carbon units. The key steps in the pathway are:

  • two phosphorylation reactions to form fructose bisphosphate;
  • cleavage of fructose bisphosphate to yield two molecules of triose (three-carbon sugar) phosphate;
  • two steps in which phosphate is transferred from a substrate onto ADP, forming ATP (and hence a yield of 4 X ATP per mole of glucose metabolized);
  • one step in which NAD+ is reduced to NADH (equivalent to 3 X ATP per mol of triose phosphate metabolized, or 6 X ATP per mol of glucose metabolized when the NADH is reoxidized in the mitochondrial electron transport chain) (section 3.3.1.2);
  • formation of 2 mol of pyruvate per mole of glucose metabolized.

The immediate substrate for glycolysis is glucose 6-phosphate. As shown in Figure 5.9, this may arise from two sources:

  • by phosphorylation of glucose, catalysed by hexokinase (and also by glucokinase in the liver in the fed state; section 5.3.1);
  • by phosphorolysis of glycogen in liver and muscle to yield glucose 1-phosphate, catalysed by glycogen phosphorylase; glucose 1-phosphate is readily isomerized to glucose 6-phosphate.

The pathway of glycolysis is shown in Figure 5.10. Although the aim of glucose oxidation is to phosphorylate ADP to ATP, the pathway involves two steps in which ATP is used, one to form glucose 6-phosphate when glucose is the substrate and the other to form fructose bisphosphate. In other words, there is a modest cost of ATP to initiate the metabolism of glucose.

As discussed in section 10.2.2, the formation of fructose bisphosphate, catalysed by phosphofructokinase, is an important step for the regulation of glucose metabolism. Once it has been formed, fructose bisphosphate is cleaved into two three-carbon compounds, which are interconvertible. The metabolism of these three-carbon sugars is linked to both the reduction of NAD+ to NADH and direct (substrate-level) phosphorylation of ADP to ATP (section 3.3). The result is the formation of 2 mol of pyruvate from each mole of glucose.

The oxidation of glucose to pyruvate thus requires the utilization of 2 mol of ATP (giving ADP) per mole of glucose metabolized, but yields 4 X ATP by direct phosphorylation of ADP, and 2 X NADH (formed from NAD+), which is equivalent

CH2OH

CHoOH

CH9OH

CH2OH

CHoOH

CH9OH

glycogen phosphorylase glucose 1-phosphate

Glycolysis Ch2oh Atp Adp

glucose 1-phosphate glucose

Figure 5.9 Sources of glucose 6-phosphate for glycolysis.

glucose 6-phosphate glucose

Figure 5.9 Sources of glucose 6-phosphate for glycolysis.

hexokinase ADP

ch2oh glucose

h3po4

glucose

6-phosphatase hc=0

glucose 6-phosphate phosphohexose isomerase

CH2OH I

phosphofructokinase ADP

h3po4

ch20-(f) fructose 1,6

ch2oh dlhydroxyacetone phosphate triose phosphate isomerase bisphosphatase fructose 6-phosphate fructose 1,6-bisphosphate

CH,0

HC=0

glyceraldehyde 3-phosphate

2x3 carbon sugar molecules per glucose

H3PO4-.

glyceraldehyde 3-phosphate dehydrogenase

"NADH

CH3 I

COOH pyruvate pyruvate kinase

COOH phosphoenolpyruvate enolase phosphoglyceromutase phosphoglycerate' ^^

CH2OH CH20-{^pN) kinase CH20-(pJ

blsphosphoglycerate

COOH 2-phosphoglycerate

COOH 'f

3-phosphoglycerate ATP

Figure 5.10 Glycolysis.

to a further 6 X ATP when oxidized in the electron transport chain (section 3.3.2). There is thus a net yield of 8 X ADP + phosphate ^ ATP from the oxidation of 1 mol of glucose to 2 mol of pyruvate.

As discussed in section 5.7, the reverse of the glycolytic pathway is important as a means of glucose synthesis — the process of gluconeogenesis. Most of the reactions of glycolysis are readily reversible, but at three points (the reactions catalysed by hexokinase, phosphofructokinase and pyruvate kinase) there are separate enzymes involved in glycolysis and gluconeogenesis.

For all of these reactions, the equilibrium is in the direction of glycolysis, because of the utilization of ATP in the reaction and the high ratio of ATP to ADP in the cell. The reactions of phosphofructokinase and hexokinase are reversed in gluconeogenesis by simple hydrolysis of fructose bisphosphate to fructose 6-phosphate plus phosphate (catalysed by fructose bisphosphatase) and of glucose 6-phosphate to glucose plus phosphate (catalysed by glucose 6-phosphatase).

The equilibrium of pyruvate kinase is also strongly in the direction of glycolysis, because the immediate product of the reaction is enolpyruvate, which is chemically unstable. As shown in Figure 5.31, enolpyruvate undergoes a non-enzymic reaction to yield pyruvate. This means that little of the product of the enzymic reaction is available to undergo the reverse reaction in the direction of gluconeogenesis. The conversion of pyruvate to phosphoenolpyruvate in gluconeogenesis is discussed in section 5.7.

The glycolytic pathway also provides a route for the metabolism of fructose, galactose (which undergoes phosphorylation to galactose 1-phosphate and isomerization to glucose 1-phosphate) and glycerol. Some fructose is phosphorylated directly to fructose 6-phosphate by hexokinase, but most is phosphorylated to fructose 1-phosphate by a specific enzyme, fructokinase. Fructose 1-phosphate is then cleaved to yield dihydroxyacetone phosphate and glyceraldehyde; the glyceraldehyde can be phosphorylated to glyceraldehyde 3-phosphate by triose kinase.

Glycerol arising from the hydrolysis of triacylglycerols can be phosphorylated and oxidized to dihydroxyacetone phosphate. In triacylglycerol synthesis (section 5.6.1.2), most glycerol phosphate is formed from dihydroxyacetone phosphate.

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